Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O1CCCC1>CO>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
To a mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g) in methanol (10.0 ml) were added conc. hydrochloric acid (0.52 g) and tetrahydrofuran (5.0 g) and the mixture was stirred for 2 hours and 10 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate and then the resulting mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated, washed with ethyl acetate (×2) and then concentrated. The concentrate was adjusted to pH 3.0 with 10% hydrochloric acid and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[OH-].[Na+].[CH3:19]OCCOC.CI>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:19])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COCCOC
Reactant: COC(=O)Cc1ccc2cc(C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: CCO
Product: COC(=O)C(C)c1ccc2cc(C)ccc2c1

Procedure:
To a mixture of 22 g. of methyl 6-methyl-2-naphthylacetate, 2.5 g. of sodium hydroxide and 150 ml. of 1,2-dimethoxyethane, 25 g. of methyl iodide are added. The reaction mixture is allowed to stand for several hours and is then diluted with ethanol followed by water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to yield methyl 6-methyl-2-naphthyl-α-methylacetate. This derivative is hydrolyzed by treatment with sodium carbonate in aqueous methanol, and the reaction mixture is acidified with hydrochloric acid, washed, dried and evaporated to dryness to yield 2-(6'-methyl-2'-naphthyl)propionic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH3:15])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16][CH3:17]>>[I-:16].[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH3:15])[N+:10]([CH3:17])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cn(Cc2ccccc2)nn1
Reactant: CI
Product: CCCc1cn(Cc2ccccc2)n[n+]1C
Product: [I-]
Temperature: 40 °C

Procedure:
1-benzyl-4-propyl-1H-1,2,3-triazole prepared above and excess iodomethane were added to a 20 mL vial. The reaction was heated at 40° C. for 3 days. The iodomethane was allowed to evaporate in the hood. The crude product was dissolved with 2 mL CH2Cl2 under reflux. The solution was precipitated into a mixture of acetone, ethyl acetate and hexane and dried in vacuo. The following structure was confirmed:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=1[CH3:29]>CN(C=O)C.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:23][C:22]=1[CH3:29]
Reactant: Cc1cc(CCl)ccc1Br
Reactant: COC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To flask containing methyl 3-(3-hydroxyphenyl)propanoate (available from Aagile Labs Division of Tyger Scientific) (0.25 g, 1.387 mmol) and cesium carbonate (0.5876 g, 1.804 mmol) in DMF (8 mL), was added 1.2 (0.3654 g, 1.665 mmol). The resulting mixture was then stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/hexane) to provide 1.3 (0.4575 g, 90.78% yield). MS ESI (pos.) m/e: 382.0 (M+H2O)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]3=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([NH:29][NH2:30])(=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)=[N:29][N:30]=[C:15]34)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCCC1Cc1noc(-c2cccc(Cl)c2)n1
Reactant: NNC(=O)c1ccncc1
Solvent: ClCCl
Product: Clc1cccc(-c2nc(CC3CCCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
37 mg (0.25 mmol) Me3OBF4 was added to a solution of 60 mg (0.21 mmol) 3-[5-(3-chloro -phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one in 2 ml CH2Cl2. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2, washed with NaHCO3 (sat), dried and concentrated. The residue was dissolved in 3 ml EtOH and 22 mg (0.16 mmol) isonicotinic hydrazide was added. The solution was heated with microwaves at 120° C. for 10 min. The reaction mixture was cooled and the volatiles were removed under reduced pressure. The crude product was purified by preparative HPLC to afford 17 mg (20%) of the desired product. 1H NMR (CDCl3):d ppm 1.75 (m, 1 H) 1.99 (m, 1 H) 2.21 (m, 2 H) 3.16 (dd, 1 H) 3.73 (m, 1 H) 3.85 (dd, 1 H) 4.07 (m, 1 H) 4.19 (m, 1 H) 7.47 (t, 1 H) 7.56 (m, 1 H) 7.67 (m, 2 H) 8.01 (m, 1 H) 8.11 m, 1 H) 8.76 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1nccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2nccc3ccccc23)CC1
Yield: 10.2 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (15 mg), an off-white solid, in 10% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]2[C:8](=[O:24])[N:9]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:10][C:6]=2[CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]2[C:8](=[O:24])[N:9]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)n1sc2cc([N+](=O)[O-])ccc2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@@H](C(=O)OCC)n1sc2cc(N)ccc2c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A solution of diethyl (S)-2-(2,3-dihydro-6-nitro-3-oxo-1,2-benzisothiazol-2-yl)glutarate (4.0 g, 10 mmol) and suspended iron (1.0 g, 18 mmol) in acetic acid (100 ml) was stirred under nitrogen for 1 hour at 55° C. Additional iron (3×0.25 g, 13 mmol) was added at intervals of 1, 1.25, and 1.75 hours. The reaction mixture was stirred 30 minutes after the last addition, filtered, concentrated in vacuo, and the residue absorbed onto silica gel (20 g) from a methylene chloride solution. Purification by chromatography on silica gel (150 g) eluting with ethyl acetate:hexane (1:1→2:1) gave diethyl (S)-2-(6-amino-2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl)glutarate (3.3 g) as an oil. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.17 (t, J=7 Hz, 3H, ester CH3), 1.95-2.38 (m, 4H, glu CH2CH2), 4.02 (q, J=7 Hz, 2H, ester CH2), 4.13 (q, J=7 Hz, 2H, ester CH2), 5.08-5.15 (m, 1H, glu CH), 6.09 (br s, 2H, NH2), 6.62 (dd, J=9,2 Hz, 1H, Ar), 6.84 (d, J=2 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 1H, Ar). Mass spectrum (CI-CH4): 353 (M+1, 100%). Anal. Calculated for C16H20N2O5S: C, 54.53; H, 5.72; N, 7.95; S, 9.10. Found: C, 54.34; H, 5.73; N, 7.87; S, 9.00.
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:26])([F:25])[F:24])[C:14]=1[C:29]([OH:31])=O.ON1C2C=CC=CC=2N=N1.Cl.[NH:43]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[CH3:44].C(N(CC)CC)C>CN(C=O)C.O>[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:25])([F:24])[F:26])[C:14]=1[C:29]([N:43]([CH3:44])[CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:31]
Reactant: COc1ccc2c(C(=O)O)c(Br)ccc2c1C(F)(F)F
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 0.33 h
Yield: 75 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (7.91 g, 1.2 eq) was added to a stirred solution of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid, prepared by the process of Example 14, Step 2 (12.00 g, 34.4 mmol) and 1-hydroxybenzotriazole (6.97 g, 1.5 eq) in anhydrous DMF (105 mL) at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 20 minutes. After 1 hour, a suspension of methyl sarcosinate hydrochloride (9.56 g, 2.0 eq) in anhydrous DMF (60 mL) was added to the reaction mixture followed by triethylamine (15.8 mL, 3.3 eq). After 21/2 hours, more triethylamine (4.8 mL, 1.0 eq) was added. The reaction was diluted with water (1.6 L) after 181/2 hours. The aqueous phase was extracted with ether (4×250 mL). The extracts were combined and washed with 0.5N sodium hydroxide solution (1×200 mL) and saturated aqueous sodium chloride (1×200 mL). The ether phase was dried with magnesium sulfate and the ether was removed. The crude product was flash chromatographed (3:2 to 2:3 petroleum ether:ethyl acetate eluent gradient, silica) then reflash chromatographed (99:1 to 9:1 methylene chloride:acetonitrile eluent gradient, silica) to provide the product as a white foam (11.16 g, 75%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH3:32].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[C:36]([OH:38])(=[O:37])[CH3:35].[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:36](=[O:37])[CH2:35][CH2:34][N:33]([CH2:39][CH3:40])[CH2:31][CH3:32])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CCN(CC)CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CCN(CC)CCC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 3-(diethylamino)propionic acid hydrochloride (0.0032 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-3-(diethylamino)-1-propanone acetate (0.038 g, 0.00006 mol).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>O>[NH:12]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]1([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8]3)[CH2:4]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc(NC2C3CC4CC(C3)CC2(Nc2ccccc2)C4)cc1
Temperature: 200 °C
Yield: 18.1 %

Procedure:
A mixture of 13 g of 2-adamantanone, 55 g of aniline, and 15 g of aniline hydrochloride was introduced to a flask with a water remover. The mixture was heated and refluxed at 200° C. (oil bath) under nitrogen atmosphere. Forty hours later, a KOH solution was added so that the pH was approximately 10, and the mixture was extracted with chloroform and washed with water. The mixture was then dried with sodium sulfate, evaporated, and purified with silica gel column chromatography, to obtain 5 g of dianilinoadamantane as a colorless amorphous material.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:10][CH:9]=3.C[Li].C([Li])CCC.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].B(F)(F)F.CCOCC>C1COCC1>[CH:19]1([CH2:18][CH2:17][O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([CH2:29][C:30]([CH3:32])([OH:33])[CH3:31])=[CH:15][C:14]3=2)[CH2:21][CH2:20]1
Reactant: Brc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Reactant: CC1(C)CO1
Agent: FB(F)F
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of 3-bromo-6-(2-cyclopropylethoxy)phenanthrene (11 mmol) from Step 1 above in THF (75 mL) at −78° C. was successively added methyllithium (1.6 M in diethyl ether, 1 mL) and butyllithium (2.5 M in hexanes, 5.3 mL). The mixture was stirred at −78° C. for 30 minutes, after which isobutylene oxide (2.9 mL, 33 mmol) was added, followed by BF3.OEt2 (4.2 mL, 33 mmol). The reaction mixture was stirred at −78° C. for 1 h, then quenched with 1 M HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layer washed with brine, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (10% ethyl acetate in hexanes) to afford 1-[6-(2-cyclopropylethoxy)-3-phenanthryl]-2-methylpropan-2-ol (1.33 g) as a yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[Cl:27]Cl.O>C(O)(=O)C>[Cl:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: ClCl
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiazin-3-one in 12.5 liters of glacial acetic acid was added 1.25 kg of potassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 liters of H2O with vigorous stirring. The 4-chloro-3H-phenothiazin-3-one which precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned off and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chloro-3H-phenothiazin-3-one which was recrystallized from toluene. m.p.: 221° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH2:17][CH3:18])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=1[O:16][CH2:17][CH3:18])[CH3:7]
Reactant: CCOc1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(Br)cc1OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl bromoacetate (1.038 mL) was added to a mixture of 4-bromo-2-ethoxyphenol (1.694 g) and potassium carbonate (1.618 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford ethyl(4-bromo-2-ethoxyphenoxy)acetate (2.26 g).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([OH:23])[C:6]=1[OH:24])=[O:4].[C:26](OC(=O)C)(=[O:28])[CH3:27].[CH3:33][C:34]([O-])=[O:35].[Na+]>CCOCC>[C:26]([O:24][C:6]1[C:7]([O:23][C:34](=[O:35])[CH3:33])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]=1[C:3](=[O:4])[N:2]([CH3:1])[CH3:25])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1c(OC(C)=O)c(OC(C)=O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (120 mg, 0.35 mmol) in acetic anhydride (1 mL, 10.6 mmol) was added NaOAc (90 mg, 1.06 mmol), the suspension was stirred at 100° C. for 2 h. The reaction mixture was partitioned between DCM (25 mL) and iced water (25 mL), dried (MgSO4), filtered and volatiles removed in vacuo to afford a colourless oil. Trituration of the colourless oil from Et2O gave 2-(dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl diacetate (UL1-044) (80 mg, 52%) as a white solid: m/z 433 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.27-7.11 (2H, m), 7.00-6.88 (2H, m), 4.00 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 2.79 (s, 3H), 2.71 (s, 3H), 2.26 (s, 6H) 1.05 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][F:9])[N:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:22])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:9][CH2:8][CH2:7][N:6]1[C:2]([NH:1][C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:3]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn(CCF)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn(CCF)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of tert-butyl (3-{[5-amino-1-(2-fluoroethyl)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (2.3 g) in N,N-dimethylformamide (12 ml) were added triethylamine (1.48 g), 4-dimethylaminopyridine (35.6 mg) and trityl chloride (2.2 g) at room temperature. The reaction mixture was stirred for 2 hours, and water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Acetonitrile was added, and the precipitate was collected by filtration to give tert-butyl (3-{[1-(2-fluoroethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH:13]([OH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1.O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:14][CH2:13][OH:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(O)Cl
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: OCCOc1cccc2cccnc12
Yield: 29.1 %

Procedure:
A mixture of 14.5 g (0.10 mole) of 8-hydroxyquinoline, 13.5 ml (0.20 mole) of chloroethanol, 40 g (0.30 mole) of potassium carbonate, and 200 ml of acetone was stirred at reflux temperature for 26 hr. The mixture was filtered and the filtrate concentrated to an oil. The oil was partitioned between toluene and aqueous potassium carbonate solution. When the toluene solution was shaken with a fresh portion of potassium carbonate solution, an off-white solid crystallized out of solution. The solid was collected by filtration and the organic layer of the filtrate extracted twice with potassium carbonate solution. The toluene solution was concentrated to obtain a black oil. The oil was redissolved in toluene and upon treating the solution with a few drops of water, a solid crystallized from solution. This solid was collected by filtration and combined with the previously obtained solid. The solid was dissolved in hot methylene chloride, stirred with magnesium sulfate and charcoal, filtered, and concentrated to an oil. The oil was crystallized by dissolving in toluene and wetting the solution with a few drops of water, affording two crops of solid (5.5 g) which was shown by 1H nmr to be a dihydrate. The dihydrate was dissolved in a mixture of methylene chloride and toluene. The solution was dried (sodium sulfate), and concentrated to give 5.4 g of the anhydrous product as an oil.